SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.
SPTLC1 variants associated with ALS produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins.
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DOI：
10.1172/jci161908
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发表时间：
2022-09-15
影响因子：
15.9
通讯作者：
Hornemann, Thorsten
中科院分区：
文献类型：
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作者：
Lone, Museer A.;Aaltonen, Mari J.;Zidell, Aliza;Pedro, Helio F.;Saute, Jonas A. Morales;Mathew, Shalett;Mohassel, Payam;Bonnemann, Carsten G.;Shoubridge, Eric A.;Hornemann, Thorsten
肌萎缩侧索硬化症（ALS）是一种影响运动神经元的进行性神经退行性疾病。丝氨酸棕榈酰转移酶（SPT）的SPTLC 1亚基的突变导致儿童期发作的ALS，该亚基催化鞘脂（SL）从头合成的第一步。SPTLC 1-ALS变体映射到与ORMDL蛋白相互作用的跨膜结构域，ORMDL蛋白是SPT活性的负调节因子。我们表明，ORMDL结合全酶复合物受损的细胞表达致病性SPTLC 1-ALS等位基因，导致增加SL合成和独特的脂质签名。C-末端SPTLC 1变异体由于1-脱氧鞘脂（1-deoxySL）的合成而导致1型周围遗传性感觉和自主神经病变（HSAN 1），该鞘脂在SPT代谢L-丙氨酸而不是L-丝氨酸时形成。在SPTLC 1-ALS表达细胞中限制L-丝氨酸的可用性增加了1-脱氧SL，并将SL谱从ALS转变为HSAN 1样特征。这种效应在SPTLC 1-ALS家系中得到证实，其中索引患者独特地呈现HSAN 1表型、增加的1-脱氧SL水平和L-丝氨酸缺乏。这些数据表明SPTLC 1不同结构域中的致病性变体如何引起不同的临床表现，尽管如此，这些临床表现仍可通过底物可用性来改变。
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS–expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.